dr ranjith mp.statins for primary prevention of coronary heart disease
TRANSCRIPT
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Dr Ranjith MP
Senior Resident
Department of Cardiology
Government Medical college
Kozhikode
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INTRODUCTION
Primary prevention is treating hypercholesterolemia inpatients who do not have clinical evidence of CAD
What is the rationale for this approach ?
Grundy et al. Recent Clinical
Trials and NCEP ATP III ,
JACC Vol. 44, No. 3, 2004
August 4, 2004:720–32
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STATINS
Inhibit HMG-CoA reductase
Statin Pleiotropy
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Earlier Clinical Trials
WHO Cooperative Trial (clofibrate ) - 10,577 patients
Lipid Research Clinics Coronary Primary Prevention Trial(cholestyramine) - 3806 patients
Helsinki Heart Study (gemfibrozil ) - 4081 patients
These trials demonstrated
Significant reductions in coronary events (25, 19 & 34 %respectively)
No reduction in coronary mortality
Increase in mortality from noncardiovascular causes
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West of Scotland Coronary Prevention Study (WOSCOPS)
Designed to determine whether the administration ofpravastatin to men with hypercholesterolemia and nohistory of myocardial infarction reduced the combinedincidence of nonfatal myocardial infarction and deathfrom coronary heart disease
James Shepherd, et al, N Engl J Med 1995;333:1301-7
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West of Scotland Coronary Prevention Study Group (WOS)
Randomized, double-blind, placebo controlled
6595 men, 45 to 64 years of age
Average follow-up of 4.9 years (seen at 3 month intervals)
Pravastatin (40 mg each evening) vs. placebo
James Shepherd, et al, N Engl J Med 1995;333:1301-7
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Baseline Characteristics (WOS)
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WOSCOPS Endpoints
Primary
Non-fatal MI or coronary heart disease death as a first event
Secondary
Non-fatal MI
Coronary heart disease death
Other Endpoints
Cardiovascular mortality
Total mortality
Coronary revascularization procedures
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WOSCOPS Reduction in Lipids
20% reduction in TC 26% reduction in LDL
12% reduction in Trigs 5% increase in HDL
100
120
140
160
180
200
6 12 18 24 30 36 42 48 54 60
Months
LD
L c
ho
leste
rol
mg
/dL
placebo (intention -to-treat)
placebo (actual treatment)
pravastatin (intention-to-treat)
pravastatin (actual treatment)
James Shepherd, et al, N Engl J Med 1995;333:1301-7
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Nonfatal MI or CHD Death(Primary Endpoint)
0
2
4
6
8
10
12
0 1 2 3 4 5 6
Years in Study
Percent
with
Events
Pravastatin
Placebo31%
Risk
Reduction
P=0.0001
James Shepherd, et al, N Engl J Med 1995;333:1301-7
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Non-Fatal MI(Secondary Endpoint)
0
2
4
6
8
10
0 1 2 3 4 5 6
Years in Study
Percent
with
Events
Pravastain Placebo
31%
Risk
Reduction
P=0.000
5
James Shepherd, et al, N Engl J Med 1995;333:1301-7
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CHD Death(Secondary Endpoint)
0
0.5
1
1.5
2
2.5
0 1 2 3 4 5 6
Years in Study
Percent
with
Events
Pravastain Placebo28%
Risk
Reduction
P=0.13
James Shepherd, et al, N Engl J Med 1995;333:1301-7
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Cardiovascular Death
0
0.5
1
1.5
2
2.5
3
3.5
0 1 2 3 4 5 6
Years in Study
Percent
with
Events
Pravastain Placebo32%
Risk
Reduction
P=0.03
3
James Shepherd, et al, N Engl J Med 1995;333:1301-7
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Total Mortality
0
1
2
3
4
5
6
0 1 2 3 4 5 6
Years in Study
Percent
with
Events
Pravastain Placebo
P=0.051
22%
Risk
Reduction
James Shepherd, et al, N Engl J Med 1995;333:1301-7
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Coronary Interventions
Intervention Placebo Pravastatin Risk
(n= 3293) (n=3302) Reductions p-value
Coronary
Angiography 128 90 31% 0.007
PTCA / CABG 80 51 37% 0.009
James Shepherd, et al, N Engl J Med 1995;333:1301-7
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WOSCOPS Results/Clinical Events
Event % Reduction p value
Nonfatal MI + CHD death 31% < 0.001
Definite nonfatal MI 31% < 0.001
Definite CHD death 28% 0.13 (NS)
Definite and suspected CHD death 33% 0.042
All cardiovascular deaths 32% 0.033
Total mortality 22% 0.051 (NS)
CABG/PTCA 37% 0.029
James Shepherd, et al, N Engl J Med 1995;333:1301-7
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WOSCOPS Conclusions
Treatment with pravastatin significantly reduced theincidence of myocardial infarction and death fromcardiovascular causes without adversely affecting therisk of death from noncardiovascular causes in menwith moderate hypercholesterolemia and no history ofmyocardial infarction
Pravastatin had no effect on noncardiovascular-relatedhospital admissions
Pravastatin therapy also resulted in a 30 percentreduction in the risk of developing diabetes
James Shepherd, et al, N Engl J Med 1995;333:1301-7
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WOS Projected Benefits
Treatment of 1000 hypercholesterolemic middle aged men with pravastatin for five years will avoid:
14 coronary angiograms
8 revascularization procedures
20 nonfatal MIs
7 CHD deaths
2 additional deaths
James Shepherd, et al, N Engl J Med 1995;333:1301-7
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Management of Elevated Cholesterol in the Primary Prevention Group of Adult Japanese
(MEGA) Trial
Diet Modification
n=3,966
Primary Endpoints: Composite of coronary heart disease events, defined as cardiac
and sudden death, fatal and nonfatal myocardial infarction (MI), angina and cardiac or
vascular intervention.
Secondary Endpoints: Stroke, CHD composite or cerebral infarction, any
cardiovascular event, total mortality.
Diet Modification + Pravastatin10-20 mg/day
n=3,866
7,832 ,men age 40-70 years and postmenopausal women up to age 70
with total cholesterol 220-270 mg/dLMean BMI 23.8 kg/m2, 21% Diabetics, 20% Current Smokers,
baseline total cholesterol 242.6 mg/dL, LDL 157 mg/dL, HDL 57.5 mg/dL, triglycerides 127 mg/dL
32% Female, Mean Age 58 years, Mean Follow-Up 5.3 years
Prospective. Randomized. Open-label.
Eishu Nango et al, lancet 2006;368:11555-63
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MEGA Trial: Cholesterol and Triglyceride Levels
-11.5
-18.0
5.8
-3.1-2.1-3.2
3.21.3
-20
-16
-12
-8
-4
0
4
Pravastatin+diet Diet
• Total cholesterol,
LDL, Triglyceride
reduction was larger
in the pravastatin
group
•HDL increase was
greater in the
pravastatin group
Total
CholesterolLDL HDL Triglycerides
mg/d
L
Eishu Nango et al, lancet 2006;368:11555-63
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MEGA Trial: Primary Composite Endpoint
3.3
5.0
0
1
2
3
4
5
Pravastatin+diet Diet
3.3 vs 5.0 per 1000 patient
years, hazard ratio 0.67,
p=0.01
Primary composite endpoint of coronary
heart disease events p = 0.01
# p
er
1000 p
ati
en
t years
Eishu Nango et al, lancet 2006;368:11555-63
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MEGA Trial: Secondary Endpoints
2.7
0.9
2.5
2.0
3.8
1.6
3.0
2.6
0
1
2
3
4
Total mortality MI Stroke Cerebral
infarction+TIAPravastatin+diet Diet
p=0.055
p=0.03
p=0.33
•Total mortality was non-significantly lower in the pravastatin group (2.7 vs 3.8, HR 0.71, p=0.055)
•MI occurred less often in the pravastatin group (0.9 vs 1.6, p=0.03)
•No significant difference was observed in stroke (2.5 vs 3.0, p=0.33) or cerebral infarction plus TIA (2.0 vs 2.6, p=0.23)
# p
er
1000 p
ati
en
t years
p=0.23
Eishu Nango et al, lancet 2006;368:11555-63
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MEGA Trial: Safety Data
5.5 5.7
0
1
2
3
4
5
6
Pravastatin+diet Diet
# p
er
10
00
pa
tie
nt
ye
ars
• There was no difference in the frequency of cancer or elevated liver function
abnormalities and no cases of rhabdomyolysis.
2.8% 2.8%
0.0%
0.5%
1.0%
1.5%
2.0%
2.5%
3.0%
Pravastatin+diet Diet%
Frequency of cancer
(per 1000 patient years)
Frequency of elevated liver function
abnormalities (%)
Eishu Nango et al, lancet 2006;368:11555-63
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MEGA Trial: Summary
Among Japanese patients with hypercholesterolemia,
treatment with pravastatin was associated with a reduction
in the primary composite endpoint of coronary heart disease
The cardiac morbidity and mortality in Japan is much
lower than in the U.S. and other western countries where
statin therapy has been predominantly studied.
The present study demonstrated that even in this lower
risk population, primary prevention with low-dose statin
therapy can be effective in reducing cardiac events, with a
modest reduction in lipid parameters.
Eishu Nango et al, lancet 2006;368:11555-63
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Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial and ALLHAT–Lipid-
Lowering Trial (ALLHAT)
N = 42,418: stage 1/2 hypertension + >1 CV risk factor
Chlorthalidone
12.5–25 mg/d
n = 15,255
Amlodipine
2.5–10 mg/d
n = 9048
Lisinopril
10–40 mg/d
n = 9054
Doxazosin*2–8 mg/d
n = 9061
ALLHAT:
Step 1: titration
Step 2: open-label atenolol 25–100 mg/d, clonidine 0.1–0.3 mg bid, reserpine 0.05–0.2 mg/d
Step 3: open-label hydralazine 25–100 mg bid
N = 10,355; CHD, LDL-C 100 to 129 mg/dL or no CHD, LDL-C 120 to 189 mg/dL
Pravastatin 40 mg/d (n = 5170) Usual care (n = 5185)
ALLHAT-LLT:
ALLHAT Collaborative Research Group.
JAMA. 2002;288:2981-2997, 2998-3007.*Arm discontinued
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ALLHAT-LLT: Effects of statin or usual care on outcomes
Cumulative
rate
(%)
6543210
0
3
6
9
12
15
18
Time to death (years) Time to event (years)
6543210
0
3
6
9
12
15
18
All-cause mortality CHD death + nonfatal MI
RR = 0.99
(95% CI, 0.89–1.11)
RR = 0.91
(95% CI, 0.79–1.04)
Pravastatin Usual care
N = 10,355 with treated hypertension, baseline LDL-C 120–189 mg/dL
(no CHD) or LDL-C 100–129 mg/dL (CHD)
At 4 yrs, LDL-C by 28% (statin) and 11% (usual care)
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ALLHAT: Clinical implications
BP-lowering trial
Diuretic, ACEI, CCB equivalent in CHD death and MI
Lipid-lowering trial (ALLHAT-LLT)
Statin, usual care equivalent in all-cause mortality
Modest differential in on-treatment cholesterol levels may have contributed to result
ALLHAT BP results support importance of BP lowering, regardless of drug class usedALLHAT-LLT results are consistent with other statin trials
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Prospective Study of Pravastatin in the Elderly at Risk (PROSPER)
5804 patients aged 70–82 years with a history of vascular disease or with cardiovascular risk factors
Randomized to pravastatin 40 mg/d or placebo
Baseline TC 155–348 mg/dL
Follow-up 3.2 years (mean)
Primary endpoint (composite): coronary death, nonfatal MI, fatal or nonfatal stroke
Shepherd J et al. Lancet 2002;360:1623–1630
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Major Endpoints: PROSPER
Endpoint
Pravastatin (%)
Placebo (%)
Hazard ratio p
Primary endpoint:
CHD death/MI/stroke 14.1 16.2 0.85 0.014
Secondary endpoints:
CHD death/MI 10.1 12.2 0.81 0.006
Fatal or nonfatal stroke 4.7 4.5 1.03 0.81
Other outcomes:
Nonfatal MI 7.7 8.7 0.86 0.10
Nonfatal stroke 4.0 4.1 0.98 0.85
Transient ischemic attack 2.7 3.5 0.75 0.051
All CV events 15.7 18.0 0.85 0.012
Shepherd J et al. Lancet 2002;360:1623–1630
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Mortality by Cause: PROSPER
Cause of death
Pravastatin
(%)
Placebo
(%)
Hazard
ratio p
CHD 3.3 4.2 0.76 0.043
Stroke 0.8 0.5 1.57 0.19
Vascular 4.7 5.4 0.85 0.16
Nonvascular 5.6 5.1 1.11 0.38
Cancer 4.0 3.1 1.28 0.082
Trauma/suicide 0.1 0.2 NA NA
All causes 10.3 10.5 0.97 0.74
Shepherd J et al. Lancet 2002;360:1623–1630Shepherd J et al. Lancet 2002;360:1623–1630
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Pravastatin given for 3 years reduced the risk of coronary disease in elderly individuals
PROSPER therefore extends to elderly individuals the treatment strategy currently used in middle aged people
Shepherd J et al. Lancet 2002;360:1623–1630
PROSPER Conclusion
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Air Force/Texas Coronary Atherosclerosis Prevention Study (AFCAPS/TexCAPS)
Randomized, double-blind, placebo-controlled trial
To compare lovastatin with placebo for prevention of the first acute major coronary event (UA, fatal and non-fatal MI and sudden cardiac death)
6605 pts without CHD , 5608 men and 997 women
Average follow-up was 5.2 years
Lovastatin (20-40 mg daily) or placebo
Downs JR, et al, JAMA 1998;279:1615-1622
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AFCAPS/TexCAPS Endpoints
Primary
First Acute Major Coronary Event (UA, Fatal or Non-fatal MI ,Sudden Cardiac Death)
Secondary
Fatal or Non-Fatal MI
Unstable Angina
Fatal or Non-Fatal Cardiovascular Events
Fatal or Non-Fatal Coronary Events
Tertiary Endpoints
Total Mortality, Non-Cardiovascular Mortality
Fatal and Non-Fatal Cancer
Discontinuation of Medication because of Adverse EffectsDowns JR, et al, JAMA 1998;279:1615-1622
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Baseline Characteristics(AFCAPS)
Downs JR, et al, JAMA 1998;279:1615-1622
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Baseline Characteristics(AFCAPS)
Downs JR, et al, JAMA 1998;279:1615-1622
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Baseline Lipid LevelsCompared with U.S. Reference Population Based Upon NHANES III
Lipid Level(mg/dL)
Wilford HallAvg + SD(mg/dL)N=6605
NHANESPercentile1
U.S. NHANES Ref.Population2
Mean + SD(mg/dL)
Mean TCMean LDLMean HDL Men WomenMedian TG
221 + 21150 + 17
36 + 540 + 5
158 + 76
5160
251663
225 + 45142 + 3750 + 16
140 + 120
1 Percentile ranks from US NHANES III reference population for study population averages2 Men aged 45-73, and women aged 55-73, without cardiovascular disease
Downs JR, et al, JAMA 1998;279:1615-1622
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AFCAPS Reduction in Lipids-year
Mean TC
Mean LDL-C
Mean HDL-C
Median TG
Ratios
Mean LDL-C/HDL-C
Mean TC/HDL-C
Placebo
228.1 + 27.7
156.4 + 24.5
37.5 + 7.9
162.8 + 82.1
4.3 + 1.1
6.3 + 2.5
Lovastatin
183.7 + 23.8
114.6 + 20.1
39.3 + 8.0
142.8 + 72.8
3.0 + 0.8
4.8 + 1.0
Downs JR, et al, JAMA 1998;279:1615-1622
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Percent Change in Lipid Parameters Baseline to Year 1
0.9 1.5 1.2
-2.3
1.7 1.6
-18.4
-25
6
-15
-21.8
-28
-40
-30
-20
-10
0
10
20
30
Pe
rce
nt
Placebo
Lovastatin, avg dose 30 mg
p-value < 0.001 for all lovastatin treatment groups
42% of lovastatin patients achieved LDL-C goal of < 110 mg/dL (placebo 3%)
81% of lovastatin patients achieved LDL-C goal of < 130 mg/dL (placebo 12%)
TC LDL HDL TG TC/HDL LDL/HDL
Downs JR, et al, JAMA 1998;279:1615-1622
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Primary Endpoint ~ First Acute Major Coronary Event*
N=3304 N=3270 N=3228 N=3184 N=3134 N=1688
Lovastatin
N=3301 N=3251 N=3211 N=3159 N=3092 N=1644
Placebo
# At Risk
Lovastatin
Placebo
0.00
0.01
0.02
0.03
0.04
0.05
0.06
Years of Follow-up0 1 2 3 4 5 5+ Years
Cu
mu
lati
ve
Inci
den
ce
37% Risk Reduction(p < 0.001)
*Includes unstable angina, fatal and non-fatal MI &sudden cardiac death
Downs JR, et al, JAMA 1998;279:1615-1622
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Primary Endpoint ~ First Acute Major Coronary Event*
40
66
100
135
183
23
46
7091
116
0
50
100
150
200
250
1 2 3 4 5+ years
Years Since Randomization
Cum
ula
tive N
um
ber
of
Part
icip
ants
wit
h E
vents
Placebo (n=3301)
Lovastatin (n=3304)
Fatal & Non-fatal MI, Unstable Angina, Sudden Cardiac
Death
reduced by 37% (p < 0.0008)
Downs JR, et al, JAMA 1998;279:1615-1622
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Lovastatin Reduced the Risk of First Acute Major Coronary Events
-37
-46
-31
-58
-38-42
-70
-60
-50
-40
-30
-20
-10
0
Pe
rce
nt
Ris
k R
ed
ucti
on
Men
N=5608
Women
N=997
> Median
by Age
N=3180
Smokers
N=818
Hypertension
N=1448
Diabetes
N=156
Downs JR, et al, JAMA 1998;279:1615-1622
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Lovastatin Reduced the Risk of First Acute Major Coronary Events in All Baseline LDL Tertiles
-34 -36-41
-60
-50
-40
-30
-20
-10
0
90.4-141.9 142.0-156.8 156.9-235.4
Pe
rce
nt
Ch
an
ge
Relative Risk Reduction
Baseline LDL Tertiles
Downs JR, et al, JAMA 1998;279:1615-1622
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AFCAPS/TexCAPSRole of Baseline LDL on Outcomes
54 52
77
3733
46
0
10
20
30
40
50
60
70
80
90
< 142, n=2210 143-156, n=2195 > 157, n=2199
Nu
mb
er o
f E
ven
ts
Placebo
Lovastatin
Baseline LDL Level (mg/dL)
Downs JR, et al, JAMA 1998;279:1615-1622
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AFCAPS/TexCAPSRole of Baseline HDL on Outcomes
7168
4440 41
35
0
10
20
30
40
50
60
70
80
< 34 35-39 > 40
Nu
mb
er o
f E
ven
ts
Placebo
Lovastatin
Baseline HDL Level (mg/dL)
Downs JR, et al, JAMA 1998;279:1615-1622
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Secondary Endpoint AnalysesFatal and Non-Fatal MI
N=3304 N=3281 N=3249 N=3214 N=3174 N=1717N=3301 N=3270 N=3237 N=3200 N=3148 N=1692
# At RiskLovastatinPlacebo
0.00
0.01
0.02
0.03
Years of Follow-up
0 1 2 3 4 5 5+ years
Lovastatin
Placebo
Cum
ula
tive Incid
ence 40% Risk Reduction
(p = 0.002)
25% Risk Reduction(p = 0.003)
Cardiovascular Events*
N=3304 N=3260 N=3206 N=3147 N=3088 N=1651
N=3301 N=3242 N=3187 N=3124 N=3045 N=1615
# At Risk
Lovastatin
Placebo
Cum
ula
tive Incid
ence
0.00
0.01
0.02
0.03
0.04
0.05
0.06
0.07
0.08
Years of Follow-up
0 1 2 3 4 5 5+ years
Lovastatin
Placebo
N=3304 N=3281 N=3250 N=3217 N=3174 N=1707
N=3301 N=3267 N=3240 N=3205 N=3150 N=1678
# At Risk
Lovastatin
Placebo
Years of Follow-up
Unstable Angina
Cum
ula
tive Incid
ence
0.00
0.01
0.02
0.03
0 1 2 3 4 5 5+ years
Lovastatin
Placebo 32% Risk Reduction(p = 0.02)
N=3304 N=3264 N=3215 N=3160 N=3106 N=1666
N=3301 N=3246 N=3201 N=3141 N=3069 N=1634
# At Risk
Lovastatin
Placebo
Coronary Events*
Cum
ula
tive Incid
ence
0.00
0.01
0.02
0.03
0.04
0.05
0.06
0.07
Years of Follow-up
0 1 2 3 4 5 5+ years
Lovastatin
Placebo 25% Risk Reduction(p = 0.006)
Downs JR, et al, JAMA 1998;279:1615-1622
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AFCAPS/TexCAPSCoronary Revascularizations
N=3304 N=3277 N=3237 N=3192 N=3148 N=1691
N=3301 N=3258 N=3221 N=3174 N=3108 N=1659
# At Risk
Lovastatin
Placebo
Lovastatin
Placebo
0.00
0.01
0.02
0.03
0.04
0.05
Years of Follow-up0 1 2 3 4 5 5+ Years
33% Risk Reduction(p = 0.001)
Cum
ula
tive
Incid
ence
Downs JR, et al, JAMA 1998;279:1615-1622
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AFCAPS/TexCAPSMortality
Placebo Lovastatin
Event n=3301 n=3304 P-value
Total Mortality 77 80 N.S.
Cardiovascular 25 17 too few*
Non-cardiovascular 52 63 N.S.
*Too few for survival analyses
Downs JR, et al, JAMA 1998;279:1615-1622
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Tertiary AnalysisFatal and Non-Fatal Cancer*
N=3304 N=3249 N=3188 N=3117 N=3059 N=1626
Lovastatin
N=3301 N=3234 N=3171 N=3105 N=3043 N=1603
Placebo
# At RiskLovastatinPlacebo
0.00
0.01
0.02
0.03
0.04
0.05
0.06
0.07
0.08
Years of Follow-up
0 1 2 3 4 5 5+ years
Cum
ula
tive I
ncid
ence
P = NS
*Excludes non-melanoma skin cancer
Downs JR, et al, JAMA 1998;279:1615-1622
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AFCAPS/TexCAPS Summary of Results
Clinical benefit
appeared within the first year of treatment and continued
was apparent for all LDL-C tertiles
Range 90-235 mg/dl
was consistent for subgroups
Women
Risk Factors - Age, DM, HTN, Smokers
Downs JR, et al, JAMA 1998;279:1615-1622
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AFCAPS/TexCAPS Conclusions
In conjunction with a prudent diet, regular exercise and risk factor modification Lovastatin 20-40 mg/day could be used to lower the risk of the first acute major coronary event for primary prevention candidates -
Men > 45 years, Women > 55 years
HDL < 50 mg/dl
LDL > 130 mg/dl
Downs JR, et al, JAMA 1998;279:1615-1622
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The Anglo-Scandinavian Cardiac outcomes Trial(ASCOT )
Multicenter trial with 2 treatment comparison
A prospective, randomized, open, blinded end point design comparing 2 antihypertensive regimen
A double blind placebo controlled trial of atorvastatin 10mg/day in the substrate of patients with total cholesterol ≤250mg/dl
Primary end point: nonfatal MI or CHD death
Planned follow up average of 5yr
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The Anglo-Scandinavian Cardiac outcomes Trial
Sever PS et al, Lancet 2003; 361:1149.
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ASCOT-LLA trial
Sever PS et al, Lancet 2003; 361:1149.
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ASCOT-LLA trial
Sever PS et al, Lancet 2003; 361:1149.
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ASCOT-LLA trial
Sever PS et al, Eur Heart J 2008;29:499–508
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ASCOT-LLA trial
Sever PS et al, Eur Heart J 2008;29:499–508
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ASCOT-LLA trial Extension
Sever PS et al, Eur Heart J 2008;29:499–508
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The Anglo-Scandinavian Cardiac OutcomesTrial: 11-year mortality follow-up of the
lipid-lowering arm in the UK
• The aim of this study was to determine the outcome benefits in those originally assigned atorvastatin in ASCOT Trial—8 years after closure of the lipid-lowering arm of the trial among the UK population
• Post trial mortality data were collected every 2-3months
Sever PS et al, Eur Heart J August 28, 2011
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ASCOT-LLA 11 year mortality study profile
Sever PS et al, Eur Heart J August 28, 2011
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ASCOT-LLA trial Extension
Sever PS et al, Eur Heart J August 28, 2011
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ASCOT-LLA trial Extension
Sever PS et al, Eur Heart J August 28, 2011
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ASCOT-LLA trial Extension
Sever PS et al, Eur Heart J August 28, 2011
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ASCOT-LLA trial Extension
Sever PS et al, Eur Heart J August 28, 2011
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Collaborative Atorvastatin Diabetes Study (CARDS)
Colhoun HM et al. Lancet 2004;364:685-696.
• Type 2 diabetes mellitus
• Men and women 40–75 years of age
• LDL-C 160 mg/dL (4.14 mmol/L)
• TG 600 mg/dL(6.78 mmol/L)
• 1 additional RF
– HTN (or on HTN treatment)
– Retinopathy
– Albuminuria
– Current smoking
Patient Population
Primary endpoint: time to first major CV event (CHD death, nonfatal MI, unstable angina, resuscitated cardiac arrest, coronary revascularization, stroke
Secondary endpoints: total mortality, any CV endpoint, lipids, and lipoproteins
2838 patients 4-year follow-up
Atorvastatin 10 mg (n=1428)
Double-blind placebo (n=1410)
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CARDS: Patient Baseline Characteristics
Placebo(n = 1410)
Atorvastatin(n = 1428)
Age
Mean (SD) years 61.8 (8.0) 61.5 (8.3)
<60 529 (38%) 558 (39%)
60–70 708 (50%) 703 (49%)
>70 173 (12%) 167 (12%)
Women 453 (32%) 456 (32%)
White ethnicity 1326 (94%) 1350 (95%)
BMI
Mean (SD), kg/m2 28.8 (3.5) 28.7 (3.6)
Obese (BMI >30 kg/m2) 538 (38%) 515 (36%)
Colhoun HM et al. Lancet 2004;364:685-696.
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Colhoun HM et al. Lancet 2004;364:685-696.
CARDS: Patient Baseline Lipids
Placebo(n = 1410)Mean (SD)
Atorvastatin(n = 1428)Mean (SD)
Total cholesterol (mg/dL)
(mmol/L)
207 (32)
5.35 (0.82)
207 (32)
5.36 (0.83)
LDL cholesterol (mg/dL)
(mmol/L)
117 (27)
3.02 (0.70)
118 (28)
3.04 (0.72)
HDL cholesterol (mg/dL)
(mmol/L)
55 (13)
1.42 (0.34)
54 (12)
1.39 (0.32)
Triglycerides* (mg/dL)
(mmol/L)
148 (104–212)
1.67 (1.17–2.40)
150 (106–212)
1.70 (1.20–2.40)
*Median (interquartile range)
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CARDS: Lipid Levels by Treatment
Colhoun HM et al. Lancet 2004;364:685-696.
0
80
160
240
Total Cholesterol (mg/dL)
Average difference 26%,
54 mg/dL; P<0.0001
Media
n T
C (
mg/d
L)*
Years of Study
0 1 2 3 4 4.50
40
80
120
160
Med
ian
LD
L-C
(m
g/d
L)*
Years of Study
0 1 2 3 4 4.5
LDL Cholesterol (mg/dL)
Average difference 40%,
46 mg/dL; P<0.0001
Atorvastatin
Atorvastatin
PlaceboPlacebo
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CARDS: Effect of Atorvastatin on the Primary Endpoint: Major CV Events Including Stroke
Colhoun HM et al. Lancet 2004;364:685-696.
0
5
10
15
Cum
ula
tive H
azard
, (%
)
Years0 1 2 3 4
Relative Risk Reduction 37% (95% CI, 17–52)P = 0.001
1410
1428
1351
1392
Placebo
Atorvastatin
4.75
1306
1361
1022
1074
651
694
305
328
Placebo127 events
Atorvastatin83 events
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CARDS: Adverse and Serious Adverse Events
Colhoun HM et al. Lancet 2004;364:685-696.
Type of Event
Patients (%) with Event
Placebo(n = 1410)
Atorvastatin 10 mg(n = 1428)
Serious adverse eventpossibly associated with study drug
20 (1.1%) 19 (1.1%)
Discontinued for AE 145 (10%) 122 (9%)
Rhabdomyolysis 0 0
Myopathy AE report 1 (0.1%) 1 (0.1%)
CPK 10 ULN 10 (0.7%) 2 (0.1%)
ALT 3 ULN 14 (1%) 17 (1%)
AST 3 ULN 4 (0.3%) 6 (0.4%)
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In patients with Type 2 DM with lower LDL-C levels, atorvastatin 10 mg daily was safe, well tolerated & significantly efficacious in reducing the risk of first CHD events
CARDS supports recommendations that made by the ADA that patients with Type 2 DM should be considered as candidates for statin treatment—even at lower LDL-C levels
CARDS Implications and Clinical Relevance
Colhoun HM et al. Lancet 2004;364:685-696.
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Primary Prevention Trials of Lipid-Altering Therapy Including Patients with Diabetes
TrialDiabetic,*
n
Total N in
StudyLipid-Altering Drug, mg/d
CHD* Risk vs Placebo in Diabetic
Patients, %
CARDS † 2,838 2,838 Atorvastatin 10 –37 (p=.001)
AFCAPS 155 6,605 Lovastatin 20–40 ‡ –44 (NS)
HPS § 2,912 7,150 Simvastatin 40 –33 (p=.0003)
ASCOT 2,532 10,305 Atorvastatin 10 –16 (NS)
PROSPER 623 5,804 Pravastatin 40 +27 (NS)
HHS 135 4,081 Gemfibrozil 1200 –68 (NS)
Bays H et al. Future Cardiology 2005;1:39-59. | Colhoun HM et al. Lancet 2004;364:685-696. | Downs JR et al. JAMA
1998;279:1615-1622. | HPS Collaborative Group. Lancet 2003;361:2005-2016. | Sever PS et al. Lancet 2003;361:1149-
1158. | Shepherd J et al. Lancet 2002;360:1623-1630. | Koskinen P et al. Diabetes Care 1992;15:820-825.
* By history† Prospective trial in diabetic subjects; others are subgroup analyses‡ Mean 30 mg/d§ Type 1 or 2 diabetes
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Measuring Effects of Intima-Media Thickness: An Evaluation of Rosuvastatin
METEOR Trial
Evaluated the effect of rosuvastatin compared with placebo on carotid intima-media thickness (CIMT) among asymptomatic patients at low risk for cardiovascular disease
Study period was two-year
Randomized controlled trial
Rosuvastatin 40 mg daily vs placebo
Crouse JR 3rd, et al, JAMA 2007; 297:1344.
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METEOR Trial: Study Design
Primary Endpoint: Annualized rate of change in maximum CIMT
Secondary Endpoint: Annualized rate of change in maximum CIMT derived
from the near and far walls of the right and left common carotid artery; the
right and left carotid bulb; the right and left internal carotid artery; and
annualized rate of change in mean CIMT for the near and far walls of the
right and left common carotid artery.
Rosuvastatin (40mg)
n=702
Placebo
n=282
984 asymptomatic patients with moderately elevated cholesterol and low risk of CVDaccording to the National Cholesterol Education Program Adult Treatment Panel III guidelines criteria (0-1 risk factor
and LDL 120-190mg/dL or > 2 risk factors and LDL 120 to <160mg/dL with a 10-year coronary heart disease risk <
10%); HDL-C <60mg/dL; triglycerides <500mg/dL; evidence of thickening of the walls of the extracranial carotid
arteries as measured by B-mode ultrasound (max CIMT between 1.2 and <3.5mm)
5:2 Randomized. Double-blinded. Placebo-controlled.
Mean age = 57 years. 40% Female.
R
6, 12, 18 and 24 mos. follow-up
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METEOR Trial: Primary Endpoint
-0.0014
0.0131
-0.005
0.000
0.005
0.010
0.015• After two years,
treatment with
rosuvastatin was
associated with a
statistically significant
reduction in the rate of
progression of CIMT
thickening in overall
carotid segments, while
the placebo group
displayed progression
(p<0.001).
Change in C
IMT
for
12 C
aro
tid A
rtery
sites
(mm
/ye
ar)
n = 702
n = 282
p < 0.001
Change in maximum CIMT with rosuvastatin vs. placebo
Rosuvastatin
Placebo
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METEOR Trial: Secondary Endpoint
-0.0039
0.0084
-0.005
0.000
0.005
0.010 • After two years,
treatment with
rosuvastatin was
associated with a
statistically significant
reduction in the rate of
progression of CIMT
thickening in common
carotid sites, while the
placebo group
displayed progression
(p<0.001).
Change in C
IMT
for
com
mon c
aro
tid s
ites (
mm
/year)
n = 702
n = 282
p < 0.001
Change in maximum CIMT with rosuvastatin vs. placebo
Rosuvastatin
Placebo
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METEOR Trial: Secondary Endpoint
-0.0040
0.0172
-0.005
0.000
0.005
0.010
0.015
0.020 • After two years,
treatment with
rosuvastatin was
associated with a
statistically significant
reduction in the rate of
progression of CIMT
thickening in carotid
bulb sites, while the
placebo group
displayed progression
(p<0.001).
Change in C
IMT
for
caro
tid b
ulb
sites (
mm
/year)
n = 702
n = 282
p < 0.001
Change in maximum CIMT with rosuvastatin vs. placebo
Rosuvastatin
Placebo
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METEOR Trial: Secondary Endpoint
0.0039
0.0145
0.000
0.005
0.010
0.015
• After two years,
treatment with
rosuvastatin was
associated with a
statistically significant
lower progression in
CIMT thickening in
internal carotid sites as
compared with the
placebo group (p=0.02)
Change in C
IMT
for
inte
rnal caro
tid a
rtery
sites
(mm
/ye
ar)
n = 702 n = 282
p = 0.02
Change in maximum CIMT with rosuvastatin vs. placebo
Rosuvastatin Placebo
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METEOR Trial: Limitations & Summary
Compared with placebo, subjects treated with rosuvastatin had a marked reduction in LDL-cholesterol (-49 versus -0.3 percent)
The study was not designed to evaluate clinical events,
It is uncertain how well changes in CIMT predict clinical events, particularly in this low risk population.
This study does not convincingly support the use of high dose statins (such as rosuvastatin 40 mg daily) for primary prevention in patients at low risk for CHD events
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Justification for the Use of statins in Primary prevention: an Intervention Trial Evaluating
Rosuvastatin (JUPITER)
JUPITER is the first large-scale, prospective study to examine the role of statin therapy in individuals with low to normal LDL-C levels, but with increased cardiovascular risk identified by elevated CRP
Nearly half of all cardiovascular events occur in patients who are apparently healthy and who have low or normal levels of LDL-C
hsCRP predicts cardiovascular disease independent of LDL-C levels
Ridker et al, NEJM 2008359:2195-07
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JUPITER
Ridker et al, NEJM 2008359:2195-07
Rosuvastatin 20 mg (N=8901) MI
Stroke
Unstable
Angina
CVD Death
CABG/PTCA
4-week
run-in
No Prior CVD or DM
Men >50, Women >60
LDL <130 mg/dL
hsCRP >2 mg/L
Placebo (N=8901)
Baseline LDLC 104 mg/dL
Baseline HDLC 49 mg/dL
Baseline hsCRP 4.2 mg/L
Women 6,800
Non-Caucasian 5,000
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Ridker et al, NEJM 2008359:2195-07
Placebo 251 /
8901
Rosuvastatin 142 /
8901
HR 0.56, 95% CI 0.46-0.69
P < 0.00001
Number Needed to Treat (NNT5) = 25
- 44 %
0 1 2 3 4
0.0
00
.02
0.0
40
.06
0.0
8
Cu
mu
lati
ve
In
cid
en
ce
Number at Risk Follow-up (years)
Rosuvastatin
Placebo
8,901 8,631 8,412 6,540 3,893 1,958 1,353 983 544 157
8,901 8,621 8,353 6,508 3,872 1,963 1,333 955 534 174
JUPITER
Primary Trial Endpoint : MI, Stroke, UA/Revascularization, CV Death
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JUPITERGrouped Components of the Primary Endpoint
Ridker et al, NEJM 2008359:2195-07
HR 0.53, CI 0.40-0.70
P < 0.00001
Rosuvastatin
Placebo
Myocardial Infarction, Stroke, or
Cardiovascular Death
Arterial Revascularization or
Hospitalization for Unstable Angina
HR 0.53, CI 0.40-0.69
P < 0.00001
0 1 2 3 4
0.0
00.0
10.0
20.0
30.0
40.0
50.0
6
Cu
mu
lati
ve I
ncid
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ce
Follow-up (years)
0 1 2 3 4
0.0
00.0
10.0
20.0
30.0
40.0
5
Cu
mu
lati
ve I
ncid
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ce
Follow-up (years)
Placebo
Rosuvastatin
- 47 %- 47 %
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JUPITERIndividual components of the Primary Endpoint
*Nonfatal MI, nonfatal stroke, revascularization, unstable angina, CV death
Endpoint Rosuvastatin Placebo HR 95%CI P
Primary Endpoint* 142 251 0.56 0.46-0.69 <0.00001
Non-fatal MI 22 62 0.35 0.22-0.58 <0.00001Any MI 31 68 0.46 0.30-0.70 <0.0002
Non-fatal Stroke 30 58 0.52 0.33-0.80 0.003Any Stroke 33 64 0.52 0.34-0.79 0.002
Revascularizationor Unstable Angina 76 143 0.53 0.40-0.70 <0.00001
MI, Stroke, CV Death 83 157 0.53 0.40-0.69 <0.00001
Ridker et al, NEJM 2008359:2195-07
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JUPITER
Primary Endpoint – Subgroup Analysis
Ridker et al, NEJM 2008359:2195-07
0.25 0.5 1.0 2.0 4.0
Rosuvastatin Superior Rosuvastatin Inferior
Men
Women
Age < 65
Age > 65
Smoker
Non-Smoker
Caucasian
Non-Caucasian
USA/Canada
Rest of World
Hypertension
No Hypertension
All Participants
N P for Interaction
11,001 0.80
6,801
8,541 0.32
9,261
2,820 0.63
14,975
12,683 0.57
5,117
6,041 0.51
11,761
10,208 0.53
7,586
17,802
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Ridker et al, NEJM 2008359:2195-07
JUPITER
Primary Endpoint – Subgroup Analysis
0.25 0.5 1.0 2.0 4.0
Rosuvastatin Superior Rosuvastatin Inferior
Family HX of CHD
No Family HX of CHD
BMI < 25 kg/m2
BMI 25-29.9 kg/m
BMI >30 kg/m
Metabolic Syndrome
No Metabolic Syndrome
Framingham Risk < 10%
Framingham Risk > 10%
hsCRP > 2 mg/L Only
All Participants
N P for Interaction
2,045 0.07
15,684
4,073 0.70
7,009
6,675
7,375 0.14
10,296
8,882 0.99
8,895
6,375
17,802
2
2
hsCRP > 2 mg/L Only 6,375
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JUPITER
Adverse Events and Measured Safety Parameters
Ridker et al, NEJM 2008359:2195-07
Event Rosuvastatin Placebo P
Muscle weakness 1,421 (16.0) 1,375 (15.4) 0.34
Myopathy 10 (0.1) 9 (0.1) 0.82
Rhabdomyolysis 1 (0.01)* 0 (0.0) --
Incident Cancer 298 (3.4) 314 (3.5) 0.51
Cancer Deaths 35 (0.4) 58 (0.7) 0.02
Hemorrhagic stroke 6 (0.1) 9 (0.1) 0.44
GFR (ml/min/1.73m2 at 12 mth) 66.8 (59.1-76.5) 66.6 (58.8-76.2) 0.02
ALT > 3xULN 23 (0.3) 17 (0.2) 0.34
Fasting glucose (24 mth) 98 (91-107) 98 (90-106) 0.12
HbA1c (% at 24 mth) 5.9 (5.7-6.1) 5.8 (5.6-6.1) 0.01
Glucosuria (12 mth) 36 (0.5) 32 (0.4) 0.64
Incident Diabetes** 270 (3.0) 216 (2.4) 0.01
*Occurred after trial completion, trauma induced. All values are median (interquartile range) or N (%)
**Physician reported
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JUPITER
Statins and the Development of Diabetes
Ridker et al, NEJM 2008359:2195-07
0.25 0.5 1.0 2 4
WOSCOPS Pravastatin
HPS Simvastatin
ASCOT-LLA Atorvastatin
JUPITER Rosuvastatin
PROVE-IT AtorvastatinVS
Pravastatin
0.70 (0.50–0.98)
1.20 (0.98–1.35)
1.20 (0.91–1.44)
1.11 (0.67–1.83)
1.25 (1.05–1.54)
Statin Better Statin Worse
HR (95% CI)
PROSPER Pravastatin 1.34 (1.06–1.68)
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JUPITER
Secondary Endpoint – All Cause Mortality
Ridker et al, NEJM 2008359:2195-07
Placebo 247 /
8901
Rosuvastatin 198 / 8901
HR 0.80, 95%CI 0.67-0.97
P= 0.02
- 20 %
0 1 2 3 4
0.0
00
.01
0.0
20
.03
0.0
40
.05
0.0
6
Cu
mu
lati
ve
In
cid
en
ce
Number at RiskFollow-up (years)
Rosuvastatin
Placebo
8,901 8,847 8,787 6,999 4,312 2,268 1,602 1,192 683 227
8,901 8,852 8,775 6,987 4,319 2,295 1,614 1,196 684 246
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JUPITERConclusions
In this trial of low LDL/high hsCRP individuals who do not currently qualify for statin therapy, rosuvastatinsignificantly reduced
All-cause mortality by 20 percent
Incident myocardial infarction, stroke, and cardiovascular death by 47 percent
Ridker et al, NEJM 2008359:2195-07
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CONCLUDE
Statin trials in primary prevention, starting with thelandmark WOSCOPS trial, have found substantialrelative reductions in cardiovascular events withoutan increase in noncardiovascular mortality
In view of the evidence, statins should be seriouslyconsidered in people with diabetes at least by age 50in men and 60 in women
Also, men aged 55 years or above with multiple riskfactors, and women aged 65 years or above, should beseriously considered for generic statin use.
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THANK YOU